This study examined the therapeutic effect of magnesium (Mg) on noise trauma in anesthetized guinea pigs exposed to an impulse noise series (1/s) of Lpeak 167 dB (Leq,1s 127 dB) for 38 min. The permanent hearing threshold shift (PTS) was measured 1 week post-exposure, using auditory brain stem response audiometry (frequency range, 0.5-32 kHz). The total Mg concentrations of perilymph, cerebrospinal fluid and plasma were analyzed by atomic absorption spectrometry. In a first series, animals maintained on physiologically low Mg received subcutaneous injections of either different Mg doses (0.11-0.33 mmol MgSO4/100 g per day) for 3 days and drinking water with an additive of 39 mmol MgCl2/l for 1 week or saline as a placebo and tap water alone. The treatment began immediately after the impulse noise exposure. The dose of 0.29 mmol Mg/100 g per day was found to be most effective and reduced the hearing loss by 13-20 dB compared to placebo. The PTS and the perilymph Mg level showed a close negative correlation, suggesting that the intracochlear Mg level plays an important role in bringing about these protective effects. In a second series, we tested the therapeutic efficacy as a function of the post-exposure time of onset of the optimal Mg treatment (1 min, 2 and 4 hours), using normal Mg animals. The therapeutic effect decreased with the length of time elapsed between the end of exposure and the beginning of treatment. In a parallel scanning electron microscopic test, we also found a Mg-related difference in the susceptibility of hair cell stereocilia to impulse noise exposure.

We have demonstrated in the guinea pig that preventive dietary magnesium (Mg) supplement can significantly reduce hearing loss caused by acute high-intensity impulse noise exposure (by simulated small-arms noise) and can as well accelerate partial recovery from auditory impairment (Scheibe et al., 1994, 2000a). In parallel studies, we found Mg prophylaxis also to reduce noise-induced impairment of cochlear microcirculation (Scheibe & Haupt, 1997) and oxygenation (Scheibe et al., 2000b), as well as to decrease blood viscosity (Scheibe et al., 2000c). Moreover, preventive oral Mg supplement has also been found to reduce auditory noise-induced impairment in humans (Attias et al., 1994, 1998). The purpose of the present study was to examine whether Mg might also have a therapeutic effect on noise trauma, as this would be of relevance to the treatment of noise accidents.

Materials and Methods

In a first series, anesthetized guinea pigs with a physiologically low Mg status were exposed to an impulse noise series (1/s) of L peak 167 dB (L eq,1s 127dB) for 38 min (Scheibe et al., 2000a). Immediately after the exposure, the animals received subcutaneous injections of either different Mg doses (0.11-0.33 mmol MgSO 4 /100 g per day) for 3 days and drinking water with an additive of 39 mmol MgCl 2 /l for 1 week or saline as a placebo and tap water (controls). The animals´ Mg status was analyzed with atomic absorption spectrometry (Scheibe et al., 1999). The permanent hearing threshold shift (PTS) was measured 1 week post-exposure with auditory brainstem response audiometry (0.5-32 kHz).

In a second series, we tested the time dependence of the therapeutic efficacy using normal Mg animals. The animals were treated with an Mg dose of 0.29 mmol/100 g per day, beginning either 1 min, 2 h, or 4 h post-exposure. In a few Mg and placebo animals, the inner and outer hair cell (IHC/OHC) stereocilia were examined with scanning electron microscopy.

Means ± SD/SEM were calculated for all parameters measured. The data were compared using ANOVA and Student's t-test. Pearson's correlation was calculated for the mean PTS and the Mg status of the animals (Statistica 5.5, StatSoft).

Results

Initial Mg status

The total Mg concentrations of the perilymph (PL), cerebrospinal fluid (CSF) and plasma for guinea pigs with a low or normal initial Mg status are shown in [Table - 1]. The mean Mg levels of the individual fluids differed significantly in both groups, except for CSF.

Dose dependence

No therapeutic effect was found with the initial dose of 0.11 mmol/100 g (corresponding to the maximum human dose of 80 mmol/70 kg used for general Mg therapy). For this reason, we increased the daily dose to 0.23 and 0.29 mmol/100 g [Figure - 1]. Compared to the placebo group, the hearing loss was significantly lower in both Mg-treated groups, with the difference depending on the dose given. 0.29 mmol Mg has proved to be most effective and resulted in a significant reduction by 13 to 20 dB at all frequencies tested. With 0.23 mmol, the difference was only 4 to 12 dB. The mean PTS and the Mg levels of both plasma and PL showed a negative correlation [Figure - 2]. A further increase in the Mg dose (0.33 mmol) did not improve the therapeutic effect.

Time dependence

The PTS of the Mg groups was found to be clearly dependent on the post-exposure time of the onset of treatment [Figure - 3]. When the treatment was started 1 min after the exposure, a significant reduction of the mean PTS relative to the placebo group was found, which was similar to that measured in our first series. In the 2-h group, the mean PTS was only 4-12 dB lower than that of the placebo group. When the treatment was started 4 h after the exposure (not shown in this diagram), the mean PTS was similar to that found in the 2-h animals, but the difference to the placebo group was only significant at 0.5 and 4 kHz.

Histopathology

As shown in [Figure - 4], the OHCs were much more vulnerable to noise than the IHCs, but in the Mg animals, the percentage of destroyed hair cell stereocilia was clearly lower than in the placebo animals.

Discussion

The present audiometric results are the first to demonstrate that Mg (in addition to its preventive effect) has a therapeutic effect on noise trauma. Our histological findings have confirmed this protective action. The correlation found between the PTS and the perilymphatic Mg suggests that the intracochlear Mg level plays an important role in bringing about these protective effects. The dependence of the therapeutic efficacy on the post-exposure time of the onset of treatment emphasizes the need that any kind of Mg therapy in noise trauma should be started as soon as possible after the exposure.

The specific molecular mechanisms underlying the protective effect of Mg on noise trauma have not yet been explained. It seems to be a complex process, including protection against impairment of cochlear microcirculation (Scheibe & Haupt, 1977) and oxygenation (Scheibe et al., 2000b) as well as against systemic microcirculatory impairment (Altura et al., 1992). Apart from its calcium antagonistic action, Mg as an N-methyl-D-aspartate (NMDA) antagonist which also reduces intracellular glutamate release may have an otoneuroprotective effect (Ehrenberger & Felix, 1995). Furthermore, Mg may also contribute to protecting the cochlea against free radicals (Hoane et al., 1997) which have been shown to be partly responsible for noise-induced hearing loss (Jacono et al., 1998).

In order to improve the therapeutic efficacy, further experimental studies using local application of Mg alone and in combination with another NMDA antagonist or anti-oxidant and free radical scavenger are in progress.

We think Mg as a natural and relatively cheap agent, being practically without any side effects, should more often be considered when it comes to developing both preventive and therapeutic strategies for protection against noise trauma, as it may occur in military and industrial environments.

Acknowledgement

These studies were supported by the Federal Ministry of Defence (grant InSan I 0593-V­2694), Bonn, Germany.[12]